Citations

Abstract Histologic features, presence of CDKN2A/B homozygous deletion and methylation subtype are strong determinants of outcome and of therapy in IDH-mutant gliomas. We were interested in learning if there are additional markers of outcome in these tumors. To address this question, we assembled a cohort of 963 IDH-mutant gliomas with overall survival data (median follow-up alive 2.7 years, median follow-up deceased 3.9 years). Array-based copy number data, targeted NGS, germline genotyping data and Illumina EPIC array methylation data were available on 872, 226, 542, and 401 patients, respectively. Morphologic type (oligodendroglioma versus astrocytoma, grade (2/3 vs 4) and methylation subtype (A_IDH_LG vs A_IDH_HG) were all significantly associated with survival (p <0.001). There was no significant difference in survival between grade 2 vs 3 IDH-mutant astrocytomas (p=0.53 adjusting for age and sex). However, subjects with the risk allele (G) for rs55705857 had a better overall survival than subjects with the non-risk allele (A) in IDH-mutant oligodendroglioma (AG/GG vs AA, median overall survival 21.6 vs 15.7 years, p=0.048 after adjusting for grade, age, and sex). Conversely, rs55705857 was associated with a markedly worse survival in grade 2 IDH-mutant astrocytomas (AG/GG vs AA, median overall survival 8.6 vs 19.6 years, p=0.007 after adjusting for age and sex). Despite similar sample sizes and number of deaths, there was no significant difference in overall survival by rs55705857 genotype in grade 3 or 4 IDH-mutant astrocytomas. Upon further functional analyses, TLX1 and GALNT17 were found to be differentially methylated in IDH1-mutant astrocytomas and oligodendrogliomas, respectively, when stratified by rs55705857 risk allele. This is the first observation of a germline characteristic (e.g. rs55705857) predicting survival in low-grade IDH-mutant astrocytoma. While this observation requires validation, it suggests that germline genotype may be practice changing and inform results of trials such as CATNON and CODEL.

Abstract Gliomas are heterogeneous brain tumors with prognostically-significant subtypes and few risk factors. IDH-wildtype glioblastoma, the most common subtype, carries a dismal prognosis. Using the largest GWAS dataset with histological (11,304 cases, 304,523 controls) and molecular (3,418 cases, 8,156 controls) subtypes, we analyzed the plasma and brain proteome to uncover proteins associated with glioma susceptibility. Using protein quantitative trait loci (pQTL) for 1,776 proteins in brain tissue, we identified 21 candidate proteins, including 9 associations with high probability (>70%) of colocalization (shared causal genetic variants for glioma risk and protein abundance). We confirmed known risk genes such as EGFR (p=1.9×10-35) and D2HGDH (p=1.1×10-5). We also identified novel risk proteins, including ENPP6, a choline phosphodiesterase overexpressed in glioma, for IDH-wildtype glioblastoma (OR=0.62, p=7.6×10-5), and galectin-3, a lectin encoded by a tumor fitness gene in CRISPR screens of glioma proliferation and a clinical drug target, for glioma overall (OR=1.37, p=1.3×10-5). Analyses of the plasma proteome using pQTLs for 1,362 proteins from 3 cohorts (N=88,838) identified 9 colocalized associations in whole blood. Most risk signals were subtype-specific, such as CRELD1 (p=2.5×10-5) for triple-negative glioblastoma. We found three candidate risk proteins for IDH-mutant 1p19q-intact glioma: immunoglobulin glycoprotein BCAM (p=9.6×10-8), neurotrophin receptor SorCS2 (p=3.6×10-5) and immune checkpoint PD-1 (p=1.1×10-5). Interestingly, genetically-predicted PD-1 levels had a larger effect on IDH-mutant 1p19q-intact (OR=2.75, 95% CI=1.61-4.69) than IDH-wildtype (OR=0.73, 95% CI=0.51-1.05) tumors, suggesting germline differences in immune checkpoint mechanisms among subtypes. For all colocalized candidates, genetically-predicted protein abundance was correlated with cis-regulated transcriptional activity in brain tissue. For example, genetically-predicted SORCS2 gene expression in brain tissue was associated with plasma SorCS2 levels (Z=16.1, p=1.1×10-68). Our analysis identified candidate proteins involved in immune response and neuronal proliferation, which may enable prioritization of drug targets and provide insight into disease mechanisms for glioma.

Background Advanced neuromuscular training prepares patients with anterior cruciate ligament reconstruction (ACLR) for sport participation. Return-to-sport testing often includes single-leg hop tests, yet combining motor and cognitive tasks (i.e., dual-task) might reveal neurocognitive reliance. Purpose/Hypothesis This study examined changes in performance on visuomotor reactions tests and single-leg hop tests following advanced neuromuscular training in patients with ACLR. The hypothesis was that performance would improve less on reaction tests than on single-leg hop tests. Study Design Quasi experimental, Pretest-Posttest Methods Twenty-five patients with ACLR (11 males) completed 10 sessions of advanced neuromuscular training and pre-and post-training testing. Reaction tests outcomes were from a platform and visual display. The double-leg reaction test involved touching target dots with either leg for 20 seconds; correct touches and errors were recorded. The single-leg reaction test involved hopping on the test leg to 10 target dots; hop time and errors were recorded. Single-leg hop tests included forward, triple, crossover triple, and timed hop; limb symmetry index was recorded. Effect sizes were calculated for corrected touches on the double-leg reaction test, surgical side hop time on the single-leg reaction test, and surgical side hop distance or time on single-leg hop tests. Results Correct touches on the double-leg reaction test significantly increased from pre- to post-training (20.4 +/- 4.3 vs. 23.9 +/- 2.8, p<0.001). Hop time on the single-leg reaction test significantly decreased from pre- to post-training (Surgical leg 13.2 vs. 12.3 seconds, non-surgical leg 13.0 vs. 12.1 seconds, p=0.003). Mean errors did not significantly change on either reaction test (p> 0.05). Cohens d effect sizes in descending order was single-leg hop tests (d=0.9 to 1.3), double-leg reaction test (d=0.9), and single-leg reaction test (d=0.5). Conclusion Motor performance improved after advanced neuromuscular training, but the effect size was less on visuomotor reaction tests than single-leg hop tests. The results suggest persistence of neurocognitive reliance after ACLR and a need for more dual-task challenges in training. Level of Evidence 3

Background: The new Global definition of ARDS recently introduced a subgroup known as non-intubated ARDS. This study aimed to assess the risk of progression from noninvasive oxygen support to intubation and ARDS severity based on the S pO 2 /F IO 2 among non-intubated subjects with ARDS. Methods: This retrospective study included subjects with COVID-19 admitted to 7 hospitals (5 in the United States and 2 in Argentina) from January 2020–January 2023. Subjects meeting the new non-intubated ARDS definition (high-flow nasal cannula [HFNC] with an S pO 2 /F IO 2 ≤315 [with S pO 2 ≤97%] or a P aO 2 /F IO 2 ≤300 mm Hg while receiving ≥30 L/min O 2 via HFNC) were included. The study evaluated the proportion of subjects who progressed to intubation, severity levels using the S pO 2 /F IO 2 cutoff proposed in the new ARDS definition, and mortality. Results: Nine hundred sixty-five non-intubated subjects with ARDS were included, of whom 27% ( n = 262) progressed to meet the Berlin criteria within a median of 3 d (interquartile range 2–6). The overall mortality was 23% (95% CI 20–26) ( n = 225), and among subjects who progressed to the Berlin criteria, it was 37% (95% CI 31–43) ( n = 98). Additionally, the worst S pO 2 /F IO 2 within 1 d of ARDS diagnosis was correlated with mortality, with mortality rates of 26% (95% CI 23–30) ( n = 177) for subjects with S pO 2 /F IO 2 ≤148, 17% (95% CI 12–23) ( n = 38) for those with S pO 2 /F IO 2 between 149–234, and 16% (95% CI 8–28) ( n = 10) for subjects maintaining an S pO 2 /F IO 2 higher than 235 ( P < .001). Conclusions: The non-intubated ARDS criteria encompassed a broader spectrum of subjects with lower in-hospital mortality compared to the Berlin criteria. The S pO 2 /F IO 2 and ARDS severity cutoff proposed in the new Global ARDS definition were valuable predictors of in-hospital mortality in these subjects.

AbstractObjectiveThis study aimed to evaluate the diagnostic accuracy of dried blood spot (DBS) compared with conventional serum Aquaporin‐4‐IgG (AQP4‐IgG) testing.MethodsProspective multicenter diagnostic study was conducted between April 2018 and October 2023 across medical centers in the United States, Uganda, and the Republic of Guinea. Neuromyelitis optica spectrum disorder (NMOSD) patients and controls collected blood on filter paper cards along with concurrent serum samples. These samples underwent analysis using flow cytometric live‐cell‐based assays (CBA) and enzyme‐linked immunosorbent assay (ELISA) to determine AQP4 serostatus. The accuracy of AQP4‐IgG detection between DBS and serum (gold standard) was compared.ResultsAmong 150 participants (47 cases, 103 controls), there was a strong correlation between DBS and serum samples (Spearman's correlation coefficient of 0.82). The AUC was 0.97 (95% CI: 0.92–0.99). AQP4‐IgG detection through DBS showed 87.0% sensitivity (95% CI: 0.74–0.95) and 100% specificity (95% CI: 0.96–1.00) using CBA, and 65.2% sensitivity (95% CI: 0.43–0.84) and 95.2% specificity (95% CI: 0.76–0.99) using ELISA. Serum ELISA demonstrated 69.6% sensitivity (95% CI: 0.47–0.87) and 98.4% specificity (95% CI: 0.91–0.99). The stability of DBS in detecting AQP4‐IgG persisted over 24 months for most cases.InterpretationThe DBS represents a viable alternative for detecting AQP4‐IgG in resource‐limited settings to diagnose NMOSD, offering high sensitivity and specificity comparable to serum testing. Moreover, DBS has low shipping costs, is easy to administer, and is suitable for point‐of‐care testing.

Abstract AIMS Methods for disease monitoring in glioma are currently limited. Liquid biopsies are of increasing interest within the field but have been challenging due to the blood-brain barrier. To bypass this challenge, we aimed to assess the technical and clinical feasibility of obtaining intracranial cerebrospinal fluid (CSF) for disease monitoring via cell-free DNA (cfDNA). METHOD Adults with gliomas were recruited for longitudinal intracranial CSF collection via CSF access devices, including Ommaya reservoirs in four patients and an existing VP shunt in one patient. cfDNA was then extracted and analyzed using two sequencing platforms, PredicineCARE for cancer variant profiling and PredicineSCORE for low-pass whole genome sequencing (LP-WGS). This analysis generated genomic aberration profiles and genome wide copy number burden (CNB) score. RESULTS Across five patients, thirty-five CSF samples were obtained (median volume: 3.80 mL; 0.5-5 mL), with 30 samples (85.7%) yielding sufficient cfDNA. Tumor fraction increased by 6.28x and 2.87x in two patients with radiographic disease progression and decreased by 0.08x and 0.04x in another two after chemoradiation. In another patient with pseudoprogression, tumor fraction decreased from 0.26 after resection to unmeasurable levels. Patient specific tumor-associated variant allelic frequencies (VAFs), including TP53, PTEN, and TERT, decreased within individual patients after resection and chemoradiation. In two patients with IDH-mutant gliomas, IDH1 VAF after resection correlated with decreased CSF D-2-hydroxyglutarate (D-2-HG) levels (0.64x and 0.62x, respectively, for the first patient, and 0.01x and 0.07x for the other patient). Both IDH1 VAF and D-2-HG increased in a patient with radiographic progression (2.56x and 9.21x, respectively). CNB decreased below the limit of quantification during treatment and increased above the limit at progression. CONCLUSION Longitudinal CSF cfDNA can feasibly be obtained via CSF access devices in patients with gliomas during their disease course. Further sample collection and analysis are ongoing to determine the thresholds of change indicative of treatment response and progression.

Abstract INTRODUCTION Brain tumors constitute significant morbidity and mortality in sub-Saharan Africa (SSA). Improvements in neuro-oncology practice and research have seen increased diagnosis of brain tumors. However, to our knowledge, there have been no previous projects on brain tumor genetics in SSA. To understand the feasibility of developing brain tumor biobanking and registries, this project aims to start by mapping out the current neuro-oncology capacity in terms of workforce and available services. METHODOLOGY We will conduct a descriptive questionnaire-based online survey among a cross section of neuro-oncology practitioners spread across SSA countries. The dissemination of the survey questionnaire will be facilitated by the Society for Neuro-oncology in SSA (SNOSSA). The Google designed questionnaire will capture information on the distribution, and number of available neuro-oncology care practitioners, capacity for brain tumor diagnosis and management, cancer registration, tumor biobanking, and research. CLINICAL IMPACT AND CONCLUSION This study will generate robust data from SSA, which can be used to improve future research and promote advocacy towards brain tumor diagnosis and management. This work will also serve as a pilot study for subsequent research that will focus on the development of brain tumor-specific registries and biorepositories in SSA.

AbstractObjectivesTo report lessons from integrating the methods and perspectives of clinical informatics (CI) and implementation science (IS) in the context of Improving the Management of symPtoms during and following Cancer Treatment (IMPACT) Consortium pragmatic trials.Materials and MethodsIMPACT informaticists, trialists, and implementation scientists met to identify challenges and solutions by examining robust case examples from 3 Research Centers that are deploying systematic symptom assessment and management interventions via electronic health records (EHRs). Investigators discussed data collection and CI challenges, implementation strategies, and lessons learned.ResultsCI implementation strategies and EHRs systems were utilized to collect and act upon symptoms and impairments in functioning via electronic patient-reported outcomes (ePRO) captured in ambulatory oncology settings. Limited EHR functionality and data collection capabilities constrained the ability to address IS questions. Collecting ePRO data required significant planning and organizational champions adept at navigating ambiguity.DiscussionBringing together CI and IS perspectives offers critical opportunities for monitoring and managing cancer symptoms via ePROs. Discussions between CI and IS researchers identified and addressed gaps between applied informatics implementation and theory-based IS trial and evaluation methods. The use of common terminology may foster shared mental models between CI and IS communities to enhance EHR design to more effectively facilitate ePRO implementation and clinical responses.ConclusionImplementation of ePROs in ambulatory oncology clinics benefits from common understanding of the concepts, lexicon, and incentives between CI implementers and IS researchers to facilitate and measure the results of implementation efforts.

SUMMARY Advancements in neoadjuvant regimens for esophageal adenocarcinoma have enabled some patients to achieve complete pathologic response at time of esophagectomy. There are currently limited data detailing this trend or the implications of complete pathologic response on survival. The National Cancer Database was used to identify 16,169 patients with esophageal adenocarcinoma that received trimodal therapy including esophagectomy between 2006 and 2020. Of these, 11.4% had complete pathologic response at esophagectomy. Patient factors, staging characteristics, and survival trends were evaluated. In patients diagnosed between 2016 and 2020, the rate of complete pathologic response was 17.5%. Female sex (OR 1.295, 95% CI 1.134–1.481, p = 0.0001), Black race (OR 1.729, 95% CI 1.362–2.196, p = 0.0002), Hispanic ethnicity (OR 1.418, 95% CI 1.073–1.875, p = 0.0141), and later era of diagnosis (2016–2020 OR 2.898, 95% CI 2.508–3.349, p &lt; 0.0001) were independent predictors of complete pathologic response. Clinical stage II disease was associated with an increased probability of complete pathologic response (OR 1.492, 95% CI 1.19–1.871) while clinical stage III disease had a decreased probability of complete pathologic response (OR 0.762, 95% CI 0.621–0.936, p &lt; 0.0001). Complete pathologic response conveyed a strong survival benefit, with a median survival of 86.4 months (95% CI 73.9–102.1) versus 30.7 months (95% CI 29.8–31.7, p &lt; 0.0001) in those without complete pathologic response. Four-year median survival was also higher in those with complete pathologic response (63.3%, 95% CI 60.8–66.0% vs. 39.2%, 95% CI 38.4–40.1%, p &lt; 0.0001). In summary, complete pathologic response is associated with a profound survival advantage in patients with esophageal adenocarcinoma. Such knowledge carries implications for patient counseling, prognostication, and surveillance and demonstrates a need for improved identification of complete clinical response prior to esophagectomy.